LONDON, UK (GlobalData), 17 September 2012 - As anticipated, some promising results in the Alzheimer’s field were unveiled at the recently convened congress of the European Federation of Neurological Societies (EFNS), held September 8–11. Two industry leaders, Pfizer and GE Healthcare, both announced clinical trial results that will undoubtedly impact the current landscape of Alzheimer’s research. There are two major unmet needs that currently plague the field of Alzheimer’s: the lack of therapies that actually target and impact disease progression, and a dearth of early diagnostic biomarkers and imaging tools. Pfizer’s presentation gives new hope for anti-amyloid therapies, showing that they are effective in reducing amyloid and suggesting, as many have thought, that earlier intervention may yield better clinical outcomes, albeit with major side effects. GE Healthcare’s presentation of a novel and effective amyloid imaging agent highlights how the biotech industry is responding to the need for accurate early diagnostic tools for Alzheimer’s.
Pfizer/Janssen presented data from their two recent Phase III clinical trials, one testing the anti-amyloid drug bapineuzumab in patients who carry the predisposing ApoE4 mutation, and the other testing the drug in non-carriers of ApoE4. Although the drug failed to meet the clinical endpoints of improving memory and cognitive function, follow-up data analysis shows the drug may still hold some promise. The ApoE4-carrier study involved about 1,100 people with mild-to-moderate Alzheimer’s and biomarker studies in some of these individuals indicated that bapineuzumab was effective in its targeted approach and patients had significantly less amyloid in the brain in imaging tests. Patients also showed reduced amounts of the toxic protein phosphorylated tau in their spinal fluid. Phosphorylated tau (phospho-tau) is a marker of brain cell injury associated with neurodegeneration, and the reduction of this protein could indicate a reduction in brain cell death. However, MRI tests showed that patients treated with bapineuzumab still had a similar loss of brain volume to those in the placebo group, meaning that although encouraging, reductions in phospho-tau did not translate to visible changes in brain size.
The second study included 1,331 patients with mild-to-moderate Alzheimer’s who did not carry the ApoE4 gene mutation. Follow-up biomarker studies were done in 39 of these patients and showed that bapineuzumab did not result in any significant changes in amyloid build-up, phospho-tau or brain volume. There was a slight trend in patients getting higher doses of bapineuzumab for lower phospho-tau levels and less amyloid in brain scans, but these higher doses were also associated with greater incidence of serious side effects such as fluid buildup and bleeding in the brain, as well as seizures.
In both trials, the dose-dependent side effect of brain swelling was observed in a significant number of patients. This could prove problematic since higher doses may be required for effective clearance of amyloid and reduction of phospho-tau in a way that may impact memory and cognition. A major hurdle in the development of disease-targeting central nervous system agents is the great potential for severe adverse effects such as these, where patients have to trade relief from their disease for a whole slew of unpleasant and sometimes life-threatening side effects. However, the attempt on the part of pharmaceutical companies to downplay the severity of the side effects is somewhat troubling. In the bapineuzumab trials, about 15% of patients developed fluid leaks and concomitant brain swelling compared to 0.2% of placebo patients. Additionally, 6 bapineuzumab patients developed cancer and died compared to none of those getting the placebo. Pfizer said that none of the cancers stood out and that the risk reduced when all the research data was pulled together. Brain swelling, seizures, cancer and death are hardly minor events and while there does exist a dire need for Alzheimer’s treatments, drugs should not be rushed at the expense of patient safety. It is hoped that companies such as Pfizer and others developing similar drugs will consider modifications or reformulations that may improve the safety profile of anti-amyloid drugs.
Overall, however, these study results at least show that amyloid antibody drugs are efficacious in reducing amyloid buildup in patients, and this gives the pharmaceutical industry renewed hope in the anti-amyloid approach. In fact, Roche, which is developing a similar drug called gantenerumab, just recently announced that it had more than doubled the number of patients enrolled in a Phase III clinical trial of this drug. Unlike the failed studies of Pfizer’s bapineuzumab and Lilly’s solanezumab, which were done in symptomatic Alzheimer’s patients with mild-to-moderate dementia, this study by Roche is being done much earlier in the disease and tests the anti-amyloid drug in Alzheimer's patients who do not yet have dementia. Brain scan tests have shown that gantenerumab can reduce amyloid plaques in the brain, and Roche is now strategically poised at the head of the pack in demonstrating whether early intervention will be as beneficial as postulated. Results from these trials are expected in about 3 years in 2015. However, given the fact that Alzheimer’s disease develops very slowly (taking up to 20 years), it is questionable whether 3 year trials will yield the kind of definitive clinical endpoint results required for drug approval.
The other major industry presentation on Alzheimer’s at the EFNS congress was the Phase III trial results on GE Healthcare’s amyloid imaging agent [18F]Flutemetamol. [18F]Flutemetamol is a PET imaging agent developed to detect amyloid-beta (Ab) deposits in the brain. GE Healthcare shared encouraging pooled results from Phase III brain autopsy and biopsy studies that showed that [18F]Flutemetamol PET images accurately and consistently reflected Ab levels in living patients. Currently Alzheimer’s is confirmed by performing autopsy studies which identify features such as Ab plaques in post-mortem brain samples. Amyloid targeting agents such as [18F]Flutemetamol are an important development, since better diagnostic tools for Alzheimer’s are imperative if earlier and more accurate clinical diagnoses of the disease are to be made. The presentations at this year’s EFNS congress highlight the trends in Alzheimer’s disease research that are targeting earlier diagnoses and the need for early treatments that could halt or slow disease progression.
Stockholm EFNS Congress: Progress for Alzheimer’s Following Trial Presentations
Related research: Alzheimer’s Disease Therapeutics - Global Drug Forecasts and Treatment Analysis to 2020
This expert insight was written by Dr. Sally Chege, GlobalData's analyst covering neurology. For more information, or to request an interview, please contact the press office on the details below.
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